This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A major challenge in vaccinology is that the efficacy of a vaccine can only be ascertained retrospectively, upon infection. The identification of molecular signatures, induced rapidly after vaccination, which correlate with and predict the later development of protective immunity, represent a strategy to prospectively determine vaccine efficacy. This strategy is useful when evaluating the efficacy or immunogenicity of untested vaccines, or in identifying individuals with sub-optimal responses amongst high risk populations, such as the elderly. We have recently used a systems biology approach to identify early gene signatures that predict later immune responses in humans vaccinated with the yellow fever vaccine YF-17D. This project seeks to determine the extent to which this approach will have broad utility in predicting the immunogenicity of other vaccines, and in identifying new correlates of protective immunity. We have initiated a highly collaborative effort to perform a comprehensive analysis of immune responses induced by three distinct vaccines: (i) inactivated trivalent influenza vaccine, (ii) pneumococcal polysaccharide vaccine and (iii) live attenuated varicella-zoster vaccine. These vaccines were selected for this study because influenza virus, pneumococcus, and zoster are of global public health importance and the cause of severe morbidity and mortality, especially in the elderly and other high-risk groups;all three are known to generate sub-optimal immunity in a substantial proportion of elderly vaccinees. Successful completion of this program may provide insights into defects that underlie poor vaccine efficacy in the elderly, and establish the broad utility of systems biology in predicting vaccine immunogenicity.